NEW DRUGS IN COLORECTAL-CANCER - A REVIEW OF ANTITUMOR-ACTIVITY AND CROSS-RESISTANCE PATTERNS OF TOPOISOMERASE-I INHIBITORS, THYMIDYLATE SYNTHETASE INHIBITORS, AND OXALIPLATIN

For almost three decades, 5-fluorouracil has been the only active agen t with a documented objective response rate over 10% in colorectal car cinoma. However, recently a number of new classes of antineoplastic ag ents have entered the clinic, and several of them appear to have activ ity in colorectal carcinoma. Based on biochemical considerations, spec ific inhibitors of thymidylate synthetase, namely tomudex (ZD1694), LY 231514 and AG337, have been developed which fit into the folate bindin g domain of the enzyme. Two of these, tomudex and LY231514, have demon strated activity in colon cancer in the range which can be expected fo r fluoropyrimidines. Furthermore, preclinical data indicate that speci fic thymidylate synthetase inhibitors and fluoropyrimidines display in complete cross resistance. Especially cells with acquired resistance t o these folate-based thymidylate synthetase inhibitors were, in their majority, still sensitive to 5-fluorouracil. Topoisomerase I inhibitor s possess a novel mechanism of cytotoxic action and appear to be activ e in a variety of tumors. 9-aminocamptothecin and topotecan have demon strated only limited activity in the initial trials in colorectal canc er. However, irinotecan has been extensively studied. Irinotecan is ac tive in first-line treatment with an overall response rate of 22% and, more important, shows also considerable antitumor efficacy in pretrea ted patients. A response rate of 16% was demonstrated for patients wit h documented progression on a 5-fluorouracil/folinic acid regimen, mak ing irinotecan the most active single agent for second-line therapy of colon cancer. Finally, oxaliplatin, a diaminocyclohexane-platinum(II) complex introduced into the clinic several years ago, could play an i mportant role in colon cancer. The drug shows single-agent activity in first-and second-line treatment (23% and 10% objective responses, res pectively). However, the most important feature of oxaliplatin appears to be its property to act synergistically with 5-fluorouracil. It has been demonstrated that approximately 25% of patients will respond if oxaliplatin is added to the same 5-fluorouracil regimen, once patients develop resistance to 5-fluorouracil. Taken together, the introductio n of these new drugs has clearly increased our therapeutic options in colorectal carcinoma. All of them have single-agent activity and appea r to be not cross-resistant. The task of the future will be to clearly define their exact role in the overall treatment strategy of metastat ic as well as locally advanced colorectal carcinoma.